Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients.
OBJECTIVE
Immune dysfunction is well documented in renal cell carcinoma (RCC) patients and likely contributes to tumor evasion. This dysfunction includes a shift from a type-1 to a type-2 T-cell cytokine response and enhanced T-regulatory (Treg) cell expression. Given the antitumor activity of select tyrosine kinase inhibitors such as sunitinib in metastatic RCC (mRCC) patients, it is relevant to assess their effect on the immune system.


METHODS
Type-1 (IFNgamma) and type-2 (interleukin-4) responses were assessed in T cells at baseline and day 28 of treatment with sunitinib (50 mg/d) by measuring intracellular cytokines after in vitro stimulation with anti-CD3/anti-CD28 antibodies.


RESULTS
After one cycle of treatment, there was a significant increase in the percentage of IFNgamma-producing T cells (CD3(+), P < 0.001; CD3(+)CD4(+), P = 0.001), a reduction in interleukin-4 production (CD3(+) cells, P = 0.05), and a diminished type-2 bias (P = 0.005). The increase in type-1 response may be partly related to modulation of Treg cells. The increased percentage of Treg cells noted in mRCC patients over healthy donors (P = 0.001) was reduced after treatment, although not reaching statistical significance. There was, however, an inverse correlation between the increase in type-1 response after two cycles of treatment and a decrease in the percentage of Treg cells (r = -0.64, P = 0.01). In vitro studies suggest that the effects of sunitinib on Treg cells are indirect.


CONCLUSIONS
The demonstration that sunitinib improved type-1 T-cell cytokine response in mRCC patients while reducing Treg function provides a basis for the rational combination of sunitinib and immunotherapy in mRCC.
Finke
James H
JH
Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. finkej@ccf.org
Rini
Brian
B
Ireland
Joanna
J
Rayman
Patricia
P
Richmond
Amy
A
Golshayan
Ali
A
Wood
Laura
L
Elson
Paul
P
Garcia
Jorge
J
Dreicer
Robert
R
Bukowski
Ronald
R
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007211:Indoles / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000627:therapeutic use*; D011994:Recombinant Proteins; D000077210:Sunitinib; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D000970:Antineoplastic Agents; D017252:CD3 Complex; D007211:Indoles; D011758:Pyrroles; D011994:Recombinant Proteins; D015847:Interleukin-4; D007371:Interferon-gamma; D000077210:Sunitinib